The present invention provides a series of novel 1-(biphenylmethyl)imidazole compounds which are antagonists to angiotension II (hereinafter referred to as "AII"). These compounds have valuable hypotensive activities, and which may, therefore, be used in the treatment and prophylaxis of hypertension, including diseases of the heart and circulatory system. The invention also provides methods and compositions using these compounds, as well as processes for their preparation.
It is known that the renin-angiotension system provides one of the important mechanisms for maintaining the homeostasis of blood pressure in living animals. When blood pressure is reduced or the sodium ion concentration of the body fluids falls, this system is activated. As a result, the enzyme renin and angiotensin converting enzyme (hereinafter abbreviated, as is conventional, as "ACE") are activated and act on angiotensinogen, which is first decomposed by the renin to produce angiotensin I (hereinafter abbreviated as "AI"). This AI is then converted by ACE to AII. Since AII induces strong contractions of blood vessels and accelerates the secretion of aldosterone (which is a hormone produced by the adrenal glands that controls the excretion of sodium by the kidneys and thereby maintains the balance of salt and water in the body fluids), the activation of the system results in an elevation of blood pressure. Inhibitors or suppressors of the renin-angiotension system, such as renin inhibitors, ACE inhibitors and AII antagonists, dilate blood vessels, cause lower blood pressure and improve the circulatory function, which is the basis for the use of these agents in the treatment of heart diseases.
At present only ACE inhibitors are used clinically, although renin inhibitors and AII antagonists are under investigation for such use. Of these, some peptide type AII antagonists, such as saralasin, have been known for many years, while certain non-peptide type antagonists have recently been discovered (for example, European Patent Publications No. 28 833, 28 834. 245 637, 253 310, 323 841. 324 377, 380 959, 399 732. 399 731, 400 835 and 492 105 and in Japanese Patent Application Kokai No. Sho 57-98270). Close prior art is considered to be European Patent Publications No. 253 310 and 324 377 and German Patent Publication 4 036 706.
European Patent Publication No. 253 310 discloses a series of 1-phenyl, 1-phenethyl or 1-benzyl imidazole. derivatives which are said to have the ability to inhibit the activity of AII. Included in the scope of these prior art compounds are a number of 1-biphenylmethylimidazole derivatives, which, however, differ from the compounds of the present invention in the nature of the substituent at the imidazole 4- or 5- position.
European Patent Publication No. 324 377 discloses a series of 1-(substituted phenyl)-, 1-(substituted phenethyl)- or 1-(substituted benzyl)-imidazole derivatives which are said to have the ability to inhibit the activity of All. lncluded in the scope of these prior art compounds are a number of 1-biphenylmethylimidazole derivatives, which, however, differ from the compounds of the present invention in the nature of the substituent at the imidazole 4-position.
German Patent Publication No. 4 036 706 also discloses a series of such compounds, differing from the compounds of the present invention in a similar manner. The activities of all of these prior art compounds, however, including those of European Patent Publications No. 253310 and 324 377 and German Patent Publication No. 4 036 706, are not sufficient and more potent AII antagonists are sought for better clinical results.
We have now discovered a limited series of 1-(biphenylmethyl)imidazole-5-carboxylic acid derivatives, including compounds with specific substituents at the imidazole 4-position having an excellent AII receptor antagonist activity, and which are therefore useful as antihypertensive drugs and for the therapy and prophylaxis of heart diseases.